Monitoring Prostate Thermal Therapy With Diffusion-Weighted MRI

Jing Chen,1,2* Bruce L. Daniel,2 Chris J. Diederich,4 Donna M. Bouley,3

Maurice A.A.J. van den Bosch,2 Adam M. Kinsey,4 Graham Sommer,2 andKim Butts Pauly2

For MR-guided minimally invasive therapies, it is important tohave a repeatable and reliable tissue viability evaluationmethod. The use of diffusion-weighted MRI (DWI) to evaluatetissue damage was assessed in 19 canine prostates with cryoa-blation or high-intensity ultrasound (HIU) ablation. The apparentdiffusion coefficient (ADC) trace value was measured in thetreated tissue immediately upon the procedure and on the post-treatment follow-up. For the acute lesions, the ADC value de-creased to (1.05 � 0.25) � 10–3 mm2/s, as compared to (1.64 �0.24) � 10–3 mm2/s before the treatment. There was no statis-tical difference between previously frozen or previously ultra-sound-heated lesions in terms of the 36% ADC reduction (P �0.66). The ADC decrease occurred early during the course ofthe treatment, which appears to complicate DWI-based ther-mometry. Over time, the ADC value increased as the tissuerecovered and regenerated. This study shows that DWI couldbe a promising method to monitor prostate thermal therapiesand to provide insight on tissue damage and tissue remodelingafter injury. Magn Reson Med 59:1365–1372, 2008. © 2008Wiley-Liss, Inc.

Key words: thermal therapy; magnetic resonance; diffusion-weighted MRI; cryoablation; high-intensity ultrasound; prostate

Prostate cancer is the most common cancer among Amer-ican males, accounting for one out of three cancers diag-nosed (1). The majority of asymptomatic men with pros-tate cancer have organ-confined disease (2). For thesecases, there is an increasing interest in local minimallyinvasive therapies that have potential efficacies similar tothat of radical prostatectomy and lower rates of morbidity.Options for minimally invasive therapy of the prostateinclude freezing the tissue with cryoablation (3) and heat-ing the tissue to induce tissue coagulation. Several meth-ods have been used to raise the tissue temperature, includ-ing ultrasound (4), laser (5), microwave (6), and radiofrequency (7). MRI is very promising as a guidance modal-ity for local minimally invasive therapies, because it hasthe ability to measure tissue temperature during the pro-

cedure (8–10). In clinical applications, MRI has been usedto guide thermal therapy in abdomen (11), breast (12), anduterus (13).

After completing the cryoablation or thermal ablationunder MR guidance, it is desirable to immediately evaluatethe tissue viability without relocating the patient and treat-ment applicators. This more easily facilitates a second orextended treatment if necessary. This evaluation methodshould be repeatable, which means that it could be usedagain reliably after the extended treatment. The current“gold standard” to evaluate tissue viability is contrast-enhanced MRI (CE-MRI), in which tissue lacking perfusionappears as an area lacking signal enhancement. CE-MRIprovides an excellent delineation of the necrotic tissue.However, since it involves the administration of contrastmaterials, repeat use after a second treatment is difficultdue to the previously administrated contrast material thatremains in the tissue. In addition, it cannot differentiatebetween treated areas and preexisting conditions such ascystic changes.

On the other hand, diffusion-weighted MRI (DWI) hasbeen used to assess tissue damage in many applications,including prostate cryoablation (14), high-intensity fo-cused ultrasound (HIFU)-treated uterine fibroid (15), os-teogenic sarcoma (16), and liver tumor undergoing chemo-embolization (17). DWI has been shown to be very sensi-tive to cell death and tissue damage (14–17). In addition,the DWI method can be repeated easily, which makes it anattractive technique for real time in vivo lesion evaluation.

For monitoring thermal therapy, DWI is also known tobe temperature dependent (18). However, in vivo studiesof DWI thermometry have been limited due to its highmotion sensitivity (19).

In this work, we report results from 19 canine prostatesthat have undergone cryoablation or high-intensity ultra-sound (HIU) ablation. The purpose of this study was toassess the use of DWI to estimate prostate tissue damageimmediately after thermal therapy. During the course ofthis study, we also gained enough information to providean initial report on the time course of the apparent diffu-sion coefficient (ADC) value during the weeks after treat-ment when the gland was recovering, and on the feasibilityof in vivo DWI thermometry for hyperthermic therapy.

MATERIALS AND METHODS

Surgical Model

All animal experiments were approved by Stanford Uni-versity’s Institutional Animal Care and Use Committee. Atotal of 19 adult male mixed breed dogs weighing 10.5 to

1Department of Electrical Engineering, Stanford University, Stanford, Califor-nia, USA.2Department of Radiology, Stanford University, Stanford, California, USA.3Department of Comparative Medicine, Stanford University, Stanford, Califor-nia, USA.4Department of Radiation Oncology, University of California, San Francisco,San Francisco, California, USA.Grant sponsor: National Institutes of Health (NIH); Grant numbers: R01CA111981, R01 CA092061, P41 RR009784.*Correspondence to: Jing Chen, 1201 Welch Rd., Room P064, Lucas MRS/ICenter, MC 5488, Stanford, CA 94305-5488. E-mail: jeanchen@stanford.eduReceived 1 August 2007; revised 15 January 2008; accepted 17 January2008.DOI 10.1002/mrm.21589Published online in Wiley InterScience (www.interscience.wiley.com).

Magnetic Resonance in Medicine 59:1365–1372 (2008)

© 2008 Wiley-Liss, Inc. 1365

13.3 kg were used and randomly divided into a cryoabla-tion group (N � 13) or a HIU ablation group (N � 6). Theywere given Ketamine 10 mg/kg and Valium 0.5 mg/kgmixed together intravenously as a sedative, then intubatedand maintained on 1% to 4% isoflurane gas anesthesia forthe duration of the procedure. In addition, all dogs wereplaced and maintained on an Omni-Vent ventilator (AlliedHealthcare, St. Louis, MO, USA) about 30 minutes afterintubation until imaging was completed. The antibioticCefazolin (Kefzol) 20 mg/kg was administered every 2 hduring the course of the procedure.

For the cryoablation experiments, multiple MRI compat-ible cryoprobes (Galil Medical, Westbury, NY, USA) wereinserted into the left and right lobes of the prostate throughthe anterior abdominal wall. Based on their location in theprostate, the probes were divided into two groups usingdifferent freezing schemes: one was a single slow freeze/thaw cycle (“soft freeze”); and the other was a protocolutilizing two rapid freeze/thaw cycles (“hard freeze”).Each freezing phase was manually controlled until the iceball reached a desired size on the T1-weighted gradientecho image. In this way, two distinct cryolesions werecreated in each canine prostate, for a total of 26 cryole-sions. The frozen tissue was oblong and rod-shaped. Thecoronal scan plane was chosen through the middle portionof the frozen region in order to minimize through planevariations. Three fiber optic temperature sensors (Luxtron,Santa Clara, CA, USA) were placed in the prostate tomonitor the general temperature distribution. After thecryoablation, seven dogs were killed within 3 h. The re-maining dogs survived for 4 (one dog), 14 (two dogs),21(two dogs), and 53 d (one dog), and were reimagedduring this period.

For the HIU ablation group, custom-made MR-compati-ble ultrasound devices were used (20,21). In four acuteexperiments a transurethral applicator was inserted intothe urethra with a water-cooling balloon to protect theurethral mucosa. One or more target regions were treatedin each prostate. In the other two chronic studies, twointerstitial applicators were implanted in the prostatethrough the anterior abdominal wall, creating two lesionsaway from the urethra. A total of 11 lesions were createdand monitored. The complete treatment delivery was mon-itored with real time temperature maps measured by pro-ton resonance frequency (PRF) MR thermometry. Thermaldose maps were calculated retrospectively. In one experi-ment, DWI was performed during the treatment instead ofthe PRF thermometry. A total of four dogs were euthanizedwithin 3 h, while the remaining two dogs survived for 5and 36 d, at which point they were reimaged prior to beingkilled.

MRI

All MRI was performed on the 0.5T Signa SP open MRIsystem (GE Healthcare, Milwaukee, WI, USA). The bodycoil was used as the transmitter, and an endorectal coilwas used as the receiver. The scanning plane for cryoab-lation was coronal and the one for ultrasound ablation wasaxial. Line scan diffusion-weighted imaging (LSDI) wasused as the DWI sequence (22). To evaluate the acutelesions, the LSDI was performed before the therapy and

immediately after the prostate returned to body tempera-ture after freezing or heating, as verified by the implantedfiber optic temperature sensor or the PRF thermometry.The following imaging parameters were used in LSDI: b �30 and 380 s/mm2, TE/TR � 70 ms/110 ms, bandwidth �3.91 kHz, field of view (FOV) � 24 cm � 6 cm, matrixsize � 256 � 63, effective slice thickness � 7.3 mm,number of excitation (NEX) � 1. The diffusion gradientwas applied on three orthogonal directions to calculate thediffusion trace data. The total scan time for each slice was29 s. In the DWI thermometry experiment, the diffusion-weighted images were continuously acquired at twoframes/min to monitor the complete heating process. Toreduce the motion artifact, each scan was acquired withinone single breathhold, except for the continuous DWI ther-mometry monitoring, in which free breathing wasadopted. The LSDI was followed by a three-dimensional(3D) T1-weighted fast spoiled gradient echo (FSPGR) se-quence with TE/TR � 12.6 ms/25.3 ms, bandwidth �15.63 kHz, slice thickness � 2 mm, NEX � 1, matrix size �256 � 256, and FOV varied from 12 cm to 18 cm depend-ing on the size of the prostate. The 3D sequence wasrepeated after the administration of a triple dose of gado-linium contrast material (Magnevis Berlex Laboratories,Montville, NJ) (0.3 mmol/kg). For the chronic experiments,additional MRI evaluation was performed with identicalimaging parameters as described here for the treatmentday.

Prostate Histology

After MRI, within 2 h of the LSDI, the acute animals weresacrificed and the prostates were harvested and sliced inapproximately 5-mm-thick sections along the coronalplane (cryoprostates) and axial plane (HIU prostates) sim-ilar to the MR scan plane. Fresh prostate slices were incu-bated in a 1% triphenyl tetrazolium chloride (TTC) solu-tion for 20 min, which results in viable tissue staining redand dead tissue remaining unstained. The prostate sliceswere then fixed in 10% buffered neutral formalin, pro-cessed for routine paraffin embedding and slides werestained with hematoxylin and eosin (H&E). Select sectionswere scanned by CLARiENT Inc. or BioImagene Inc. fordirect comparison with MR images.

Analysis

A large region of interest (ROI) was chosen completelywithin the necrotic tissue, and multiple ROIs were se-lected in the untreated viable tissue. These were carefullychosen to avoid the urethra, periurethral, and the lesiontransition zones (area between necrotic centers and sur-rounding completely normal tissue). Three ADC trace val-ues from: 1) the pretreatment prostate; 2) the posttreatmentuntreated tissue; and 3) the posttreatment treated tissuewere measured and shown as the mean � standard devi-ation (SD). The unpaired two-tailed Student’s t-test wasused to compare relative ADC values.

To compare the lesion size between CE-MRI and DWI, asubset of the lesions (N � 14) was chosen for analysis asthose with minimal partial volume effect. By inspectingthe 3D high-resolution FSPGR images, only lesions with

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little through-plane variation were included. Four adja-cent FSPGR slices were averaged into one single image toyield approximately the same effective slice thickness asthe LSDI slice. Histograms of the ADC values through thewhole prostate were obtained. An example shown in Fig. 1illustrates the histogram fit to a bimodal Gaussian curve.Then a threshold with minimum segmentation error wascalculated using the fitted parameters. A similar approachwas applied to outline the boundaries of heart ventricles incardioangiograms (23). After thresholding, the resultingmask was eroded with a diamond structuring element toremove small segmented regions outside the frozen area.The remaining segmented object was mapped back to thepre-erosion mask, thus delineating the “DWI lesion” inthis work. For contrast-enhanced images, the histogramdemonstrated broad lines without separation into distinctpeaks, reflecting among other factors the signal intensityshading from proximity to the coil. To segment the image,a simple edge detection program was used to segment theprostate into three regions. The region with the lowestmean was defined as the “CE lesion,” which was sur-rounded by the hyperenhancing rim with the highestmean. After segmentation, the lesion sizes were measuredon both sets of images and compared using a nonparamet-ric paired Wilcoxon signed-rank test.

RESULTS

ADC Values

Representative images of the canine prostates are shown inFig. 2 for cryoablation (Fig. 2a–e) and for HIU ablation(Fig. 2f–j). The thermally-treated lesions appeared as re-gions with low ADC value on the ADC trace maps. Thelesions on the ADC map qualitatively corresponded wellto the nonperfused regions on the CE images and the darkred areas in the TTC stained prostates. Mean trace ADCvalues are provided in Table 1 The differences in ADCtrace values were statistically significant (P � 0.0001) be-tween necrotic tissues and pretreatment viable tissues, aswell as between necrotic tissues and posttreatment viabletissues. On average, there was a 36% reduction in the ADC

of the necrotic core, contributing to a clear contrast be-tween the thermally treated tissue and the untreated tis-sue. There was no significant difference between hyper-thermic lesions and cryolesions (P � 0.66 at the signifi-cance level of 0.01), although the tissue appearance onH&E-stained sections was remarkably different, as shownin Fig. 2e and j.

Lesion Sizes

Lesion contouring is demonstrated in Fig. 3a and b. Ingeneral, the shapes of the DWI lesion and the CE lesioncorresponded well. The quantitative comparison of thelesion sizes is demonstrated in the scatter plot of Fig. 3c.Clearly separated by the identity line, the DWI lesion waslarger than the CE lesion, but smaller than the CE lesionplus the hyperenhancing rim, which usually encloses theCE lesion. As demonstrated in Fig. 3b, the DWI lesionborder extended into the hyperenhancing rim and waslocated within it. The difference in size between these twolesions was statistically significant (P � 0.01 at the signif-icant level of 0.01) as tested by paired Wilcoxon signed-rank test.

One of the cryoablation experiments clearly demon-strates the discrepancy between the DWI and the CE-MRI.In this experiment, the “soft freeze” and “hard freeze”schemes resulted in different damage level, as shown inFig. 4. The right side of the canine prostate (arrowheads)was carefully controlled to be slowly frozen to no lowerthan –10°C, which resembled the freezing process at theboundary of the ice ball; the left side (arrow) was rapidlyfrozen twice to lower than –60°C. It was believed that thelethal temperature range was between –20°C and –50°C(24). Here, a large portion of the tissue was shown ashyperenhancing region on the contrast enhanced image(arrowheads). The TTC result revealed that most of thislesion consisted of transition zone, as it appeared pink incolor indicating a mixture of viable and damaged cells.The DWI allowed differentiation within this large hyper-enhancing area. This region presented a partially reducedADC value, which was lower than the ADC of the sur-rounding untreated tissue, but higher than the ADC of thenecrotic core on the left side (arrow). The partial ADCchange was also reported by other researchers to deter-mine the necrotic fraction in the tumors (25).

FIG. 1. Histogram of the ADC trace values of a treated canineprostate, which is shown in the upper right corner. The histogramwas fitted to a mixture of two Gaussian distributions, as illustratedby the solid line. For this case, the optimal threshold value was1336.6 � 10–6 mm2/s, marked by the gray line in the figure.

Table 1ADC Trace Values of Canine Prostate Before and ImmediatelyAfter the Treatment*

PretreatmentPosttreatment

Viable Necrotic

Cryoablation 1.63 � 0.21 1.66 � 0.23 1.04 � 0.18Ultrasound ablation 1.65 � 0.30 1.78 � 0.25 1.05 � 0.34All experiments 1.64 � 0.24 1.69 � 0.24 1.05 � 0.25

*ADC (10�3mm2/s). The difference between viable and necrotictissue was statistically significant (P � 0.0001) in both sets of data.The ADC between previously heated and previously frozen tissuewas the same (P � 0.66 at the significance level of 0.01). Combiningall the experiments together, there was a 36% ADC decrease in thetreated area.

Monitoring Thermal Therapy With DWI 1367

Evolution of ADC Values

The follow-up results after the thermal treatments weremore complicated with the general trend of low initialADC values, followed by ADC values increasing over time,

as demonstrated in Fig. 5 for the cryoablation. Represen-tative images are shown in Fig. 6 for both cryoablation andHIU ablation follow-up. For the “hard freeze” lesions (ar-rows), the lesion in study #1 was still hypointense indi-cating a reduced ADC 4 d after the treatment, while itappeared to be slightly smaller in size than the acutecounterpart. Histology revealed a large central area of hem-orrhagic necrosis surrounded by a narrow rim of glandregeneration. At 14 d, the ADC map of study #2 demon-strated a small area with slightly low ADC in the “hardfreeze” region. Histology of this lesion revealed a centralregion of fibrosis and few glands surrounded by a largearea of gland regeneration. The ADC value of the “hardfreeze” lesion in study #3 increased back to normal level at53 d, with histology revealing fibrosis and regeneration ofglands, while the “soft freeze” lesion in the same dog(arrowheads) had an elevated ADC compared to normaltissue. The high ADC value in some chronic cases proba-bly indicates cystic formation; however, it is not clear whyit was observed in only some of the cases.

Studies #4 and #5 in Fig. 6 demonstrates the chroniclesions created by HIU ablation. Interestingly, 36 d afterthe hyperthermic treatment (study #5), a fluid-filled cavitywas present at the previously treated site (arrow). Thistissue loss appeared hyperintense on the ADC trace map,consistent with the fact that the cavity was filled withfreely diffusing fluid. However, this lesion resembled itsacute counterpart, an nonperfused area on the contrast-

FIG. 2. Canine cryolesions in the coronal plane (a–e) and HIU ab-lation lesions in the axial plane (f,g). Compared to the pretreatmentADC trace maps (a,f), a sharp decrease of ADC value presented inthe treated region (b,g), which corresponds to the nonperfused areaon the CE-MRI result (c,h). For the cryolesion, the dark red areas onthe TTC-stained fresh tissue (d) contains necrotic tissue and hem-orrhage. In the histology of the cryo core (H&E stain, 400�) asdemonstrated in (e), glands were completely destroyed after beingfrozen to lower than –60°C. For the ultrasound ablation lesion, akidney bean–shaped lesion is observed on all the posttreatmentresults, including ADC trace map (g), CE-MRI result (h), and TTC-stained fresh prostate (i). Interestingly, the cells are nonviable, yetappear minimally altered from untreated tissue, as shown in thehistology (H&E stain, 400�) of the “heat-fixed” region (j).

FIG. 3. Comparison of lesion size in DWI and CE imaging. The representative image in (a) shows delineation the DWI lesions on the ADCtrace map in red. The image in (b) with lesion outlines superimposed shows the DWI (red) and CE (green) contours on the contrast enhancedT1-weighted images. The overlap of the two contours is shown in yellow. The two contours are similar, with the border of the DWI lesionlocated mostly within the hyperenhancing rim. The scatter plot of lesion sizes on CE vs. DWI is demonstrated in (c), with the identity lineshown for reference. Located below the identity line, the DWI lesion is larger than the nonperfused CE region, but smaller than the CE regionplus the surrounding hyperenhancing rim.

FIG. 4. Two different cryolesions in one canine prostate. The lesionon the right side of the dog was frozen slowly to –10°C (arrowheads)while the lesion on the left was rapidly frozen to –60°C (arrow). TheTTC staining (c) indicates different degrees of damage. ADC tracemap (a) depicts both lesions with a lower ADC value of the leftlesion, while the CE-MRI (b) depicts the lesion on the right similarlyto the hyperenhancing rim.

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enhanced image. On the 5-d follow-up of study #4, twolesions with different ADC values were detected. The le-sion on the left (arrow) had a small core with a low ADC,surrounded by tissue with a normal ADC, while the lesionon the right (arrowhead) had a much lower ADC and a sizecomparable to the corresponding acute lesion. Histologyrevealed that the left lesion was hemorrhagic and under-going liquefaction and cyst formation, as in study #5,while the right lesion consisted of slightly more intacttissue with extensive hemorrhage and necrosis of glands.Compared to the left cyst-forming lesion, the right lesionwas heated with higher power for a shorter period of time.This observation is consistent with a prior report on thebody’s different response to “heat-fixed” region and tran-sition zone region in a swine renal model (26).

DWI Thermometry

At the temporal resolution of 30 s per frame, one canineprostate was treated with HIU under continuous DWImonitoring throughout the heating and the cooling phase.On the ADC trace map, the target region appeared as ele-vated ADC value during heating, as shown in Fig. 7a–c. Asthe heating continued, this high-ADC region grew in vol-ume and the ADC value kept increasing. Based on thesemiempirical relationship between diffusion and temper-ature, it was assumed that 1°C temperature change causeda 2.4% change in diffusion coefficient (18). Applying thisassumption to ADC, the temperature map was calculatedand superimposed onto the ADC map, as demonstrated inFig. 7e and f. After the whole prostate returned to body

FIG. 6. ADC trace maps from five chronic prostate lesion studies.Three dogs were killed at 4, 14, and 53 d after cryoablation, and twowere sacrificed at 5 and 36 d after HIU ablation. Each row of imagesis from a different experiment. In the cryo studies #1–#3, the arrow-heads indicate the “soft freeze” lesions, and the arrows specify the“hard freeze” lesions. At different recovery stages, the ADC valueincreases from lower than normal tissue to higher than normaltissue. For the heated lesions, the ADC value is still low at 5 d. At36 d the lesion has evolved to form a cyst, with high ADC value dueto the cyst being fluid-filled. The DWI method differentiates stagesof the lesion development, from acute necrotic tissue to cyst.

FIG. 5. Scatter plot of ADC values vs. time in chronic prostatecryolesion studies. The horizontal line represents the average nor-mal ADC value. These data show that the ADC value was initially lowafter cryoablation, and stayed significantly below normal within 1week, then gradually increased over time. In some chronic cases,the very high ADC value in the lesion probably indicates liquefactionand cyst formation.

Monitoring Thermal Therapy With DWI 1369

temperature, the acute hyperthermic lesion demonstratedlow ADC and lack of contrast enhancement, as shown inFig. 7d and g. To quantify the ADC change, three ROI werechosen, one in the core of the hyperthermic lesion, onering shape ROI at the rim of the lesion, and one in theuntreated tissue. The ADC time courses of these ROIs areplotted in Fig. 8. During heating, the change of ADC fol-lowed the trend of the applicator power. After power wasturned off, the ADC value dropped rapidly in both the coreand the rim, with the core decreased to a lower value,which was consistent with the observed ADC reduction innecrotic tissue upon the completion of the procedures. Todepict how the ADC decreased, one line of the ADC mapthrough the center of the lesion is plotted as a function oftime as shown in Fig. 7. A signal intensity dip in the core(arrowhead) is seen early in the application of the heat(arrow), although the core of the hyperthermic lesion re-mained at the highest temperature while the power wasapplied.

DISCUSSION AND CONCLUSIONS

The results of this study demonstrate the behavior of theADC of prostate tissue undergoing thermal ablation. TheADC decreased by 36% in thermally ablated prostate tis-sue, with no difference between tissues ablated with freez-ing and heating. The area of low ADC is larger than the

area of nonperfused tissue. However, the border of the lowADC area lies within the hyperenhancing rim of the lesion,as depicted on the contrast-enhanced images. ADC valuesincrease in the tissue over time as the tissue remodels. The

FIG. 7. ADC trace map acquired before heating (a), at the beginning (b) and at the end of heating (c), and at completion of the procedure(d). The low ADC region on top of the urethra was a preexisting condition, which could be seen throughout the procedure. The images in(e) and (f) are the color-encoded temperature maps calculated from (b) and (c), in which heating was applied in the left lobe. Later, anotherheating was applied in the right lobe of the prostate. The ADC map (d) and contrast-enhanced T1-weighted image (g) were acquired afterthe two heatings, and both thermal lesions showed on (d) and (g). There is a clear correlation between the heated region and the thermallesion. To demonstrate the competing effects, the evolution of the ADC value in one line across the lesion center is plotted. A signal dip(arrow) appears during heating where it is supposed to have the highest temperature. This location corresponds to the thermal lesion shownafter the completion of the heating (arrowhead).

FIG. 8. ADC time course of the entire procedure. The ultrasoundapplicator power is plotted in the red dashed line. During heating,the change of ADC value follows the power adjustment with a smalldelay in time. Immediately after the applicator was powered off, thecore ADC decreases to a lower level compared to the rim ADC anduntreated tissue, showing the effect of thermal damage.

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immediate decrease in ADC in the thermally treated tissueis a complicating factor for MR thermometry based on ADCchanges.

The 36% decrease in ADC in thermally treated prostatetissue is similar to that seen in stroke (27). Our result isalso in agreement with a previous study of focused ultra-sound treated uterine fibroid (15), and a postmortem ratneural tissue study (28). The reduction is the same nomatter how the tissue was destroyed. This is true eventhough the tissue looks very different histologically de-pending on its thermal history (frozen or heated). In cryoa-blation, the lesion cores consisted of hemorrhage and com-plete coagulation necrosis (no recognizable glands) (Fig.2e); in the heated cores, glands appeared to be intact,hence the name “heat-fixed” (Fig. 2j). This suggests thatthe change of diffusion path, or tortuosity due to differ-ences in the cellular architecture of the tissues, might notbe sufficient to account for the entire observed ADC drop.However, the similarity of the ADC reduction in ischemicbrain tissue and in thermally treated prostate tissue im-plies that it might be attributed to a common underlyingmechanism. Interestingly, decreased ADC value—a mac-roscopic indication of reduced diffusion—is also consis-tent with the microscopic observation of heat-induced in-terruption of intracellular particle movements in HeLa S-3cells using laser-Doppler spectroscopy (29).

In addition, the increase in ADC over time as the tissueremodels is also similar to the time course observed instroke (30). On the follow-up result of 53 d, ADC valuesincreased from below normal to above normal in thechronic lesions as scar tissue proliferated and glands re-generated. In the thermally debulked region (Fig. 6), theDWI method delineated the cavitated region as a high ADCvalue from both normal and necrotic tissue, while theCE-MRI method failed to differentiate the cavity from tis-sue necrosis.

The DWI lesion boundary is in agreement with otherstudies that show the boundary of the acute damage iswithin the hyperenhancing rim (31). The discrepancy be-tween DWI and CE-MRI is due to the fact that they aremeasuring two different properties of the tissue. DWI is ameasurement of the microstructure and microfunction,while CE-MRI demonstrates the vascular occlusion, an indi-rect indicator of tissue necrosis. Moreover, contrast uptake isa dynamic process while the CE-MRI sequence is static witha scan time of several minutes. After the bolus injection, thecontrast material first concentrates in the plasma, then leaksinto the extravascular space and continues to diffuse insidethe interstitial space, including the necrotic tissue, as long asthere is a concentration difference. In this case, nonperfusedtissue, especially the tissue adjacent to the hyperenhancingrim, could be enhanced on the CE images, hence causing theCE lesion size to be underestimated.

The immediate decrease in ADC in the thermally treatedtissue might be a complicating factor for MR thermometrybased on ADC values. The observed signal dip in Fig. 7suggests that there are two competing effects—the increasein ADC due to raised temperature against the decrease inADC due to necrosis that occurs during the heating. DWIthermometry may be correct at low temperature values,but inaccurate when the tissue dies. It is possible that thedrop in ADC is a more direct indicator of the state of the

tissue than temperature. However, it is not clear how thisinformation could be separated from the temperature-based increases in ADC while the tissue is heated. In lightof the competing effects, using DWI to evaluate the treat-ment lesion should wait until the target returns to bodytemperature, which is generally within several minutesdepending on the size of the treated area. To use DWI-based thermometry, it is necessary to consider the possi-bility of ADC drop for in vivo study.

On the other hand, some tissues do not demonstrate achange in ADC when the tissue is killed, such as muscletissue (28). In these cases, DWI thermometry could be avalid method for MR thermometry. In addition, DWI ther-mometry may be a viable method for monitoring low tem-perature changes for safety purposes or hyperthermia.

DWI has the advantage over the CE-MRI method in thatit can differentiate between some preexisting conditionsand acute lesions. For example, in one experiment, a re-gion lacking contrast enhancement presented in the un-treated tissue. On the ADC map, this area had a high ADCwhile the previously frozen tissue demonstrated a lowADC. This area was later identified through histologicalanalysis as a cyst. The CE-MRI method would require acontrast material administration before the treatment toeliminate the confusion. However, a pretreatment ADCmap could be easily obtained to differentiate the treatmentresult. A T2-weighted image might detect the cyst as well.

Comparing the DWI method to the CE-MRI method, twoerrors were minimized to give a fair comparison. The firsterror was partial volume error from using different sliceprofiles and thicknesses for the two sequences. The cryo-probe created a rod-shaped frozen volume with little vari-ation along the longitudinal axis of the ellipsoid, in theanterior/posterior (A/P) direction. Obtaining an image inthe coronal plane could alleviate the slice profile differ-ence and through-plane motion problem. To account forthe slice thickness, four adjacent FSPGR slices were com-bined into one single slice to achieve a similar effectivethickness, as mentioned in the Analysis section. The sec-ond error was a motion-induced misregistration betweenthe images. The error from in-plane motion was removedby simple image registration, since the center of the cryo-probe served as an ideal control point. Translation, rota-tion, and scaling were successfully corrected with two ormore pairs of control points. Lesions imaged in the axialplane, or lesions too small to correct the partial volumeeffect were excluded from the comparison.

The LSDI sequence is robust to motion artifacts andphase artifacts, and is particularly well suited to prostateimaging given the proximity of rectal bowel gas, adjacentperistalsis, and bladder filling and contractions. However,the line scan sequence inherently has low signal-to-noiseratio since it is a 1D data acquisition method. Better imagequality of the LSDI method is always preferred, which isgenerally true for all in vivo abdominal DWI. Implement-ing the procedure at higher field strength and faster gradi-ents with newly developed techniques, including spiral(32,33), echo planar imaging (EPI)-based (34,35), or PRO-PELLER-based (36) DWI, together with parallel imaging,might improve the image quality.

In conclusion, we have demonstrated that DWI is apromising treatment evaluation method for HIU ablation

Monitoring Thermal Therapy With DWI 1371

and cryoablation. In addition, it is feasible to measuretissue temperature based on the ADC change before tissuenecrosis occurs. The evolution of the ADC value also pro-vides further information on tissue regeneration and de-velopment. Future work includes accurate registration be-tween histology and MR images, MRI monitoring of thecomplete lesion recovery process, and validation of DWIassessment after human prostate cancer treatments.

ACKNOWLEDGMENT

We thank Diane Howard, Wendy Baumgardner, and Pam-ela Hertz for assisting with the animal experiments, Aim-ing Lu for pulse programming support, and Chuck Dumou-lin and Ron Watkins for providing the endorectal coil.

REFERENCES

1. American Cancer Society. Cancer facts and figures 2006. Atlanta: Amer-ican Cancer Society; 2006.

2. Mettlin C, Murphy GP, Lee F, Littrup PJ, Chesley A, Babaian R, Badal-ament R, Kane RA, Mostofif K. Characteristics of prostate cancer de-tected in the American Cancer Society-National Prostate Cancer Detec-tion Project. J Urol 1994;152:1737–40.

3. Onik G. Imaging-guided prostate cryosurgery: state of the art. CancerControl 2001;8:522–531.

4. Cline HE, Schenck JF, Watkins RD, Hynynen K, Jolesz FA. Magneticresonance-guided thermal surgery. Magn Reson Med 1993;30:98–106.

5. Germer CT, Isbert C, Albrecht D, Roggan A, Pelz J, Ritz JP, Muller G,Buhr HJ. Laser-induced thermotherapy combined with hepatic arterialembolization in the treatment of liver tumors in a rat tumor model. SurgEndosc 1998;12:1317–1325.

6. Schwarzmaier HJ, Kahn T. Magnetic resonance imaging of microwaveinduced tissue heating. Magn Reson Med 1995;33:729–731.

7. Samulski TV, MacFall J, Zhang Y, Grant W, Charles C. Non-invasivethermometry using magnetic resonance diffusion imaging: potential forapplication in hyperthermic oncology. Int J Hyperthermia 1992;8:819–829.

8. Cline HE, Hynynen K, Hardy CJ, Watkins RD, Schenck JF, Jolesz FA.MR temperature mapping of focused ultrasound surgery. Magn ResonMed 1994;31:628–636.

9. De Poorter J, De Wagter C, De Deene Y, Thomsen C, Stahlberg F, AchtenE. Noninvasive MRI thermometry with the proton resonance frequency(PRF) method: in vivo results in human muscle. Magn Reson Med1995;33:74–81.

10. Butts K, Sinclair J, Daniel BL, Wansapura J, Pauly JM. Temperaturequantitation and mapping of frozen tissue. J Magn Reson Imaging2001;13:99–104.

11. Lewin JS, Connell CF, Duerk JL, Chung YC, Clampitt ME, Spisak J,Gazelle GS, Haaga JR. Interactive MRI-guided radiofrequency intersti-tial thermal ablation of abdominal tumors: clinical trial for evaluationof safety and feasibility. J Magn Reson Imaging 1998;8:40–47.

12. Hynynen K, Pomeroy O, Smith DN, Huber PE, McDannold NJ, Ketten-bach J, Baum J, Singer S, Jolesz F. MR imaging-guided focused ultra-sound surgery of fibroadenomas in the breast: a feasibility study. Ra-diology 2001;219:176–185.

13. Clare MT, Stewart EA, McDannold N, Quade BJ. MR imaging–guidedfocused ultrasound surgery of uterine leiomyomas: a feasibility study.Radiology 2003;226:897–905.

14. Butts K, Daniel BL, Chen L, Bouley DM, Wansapura J, Maier SE,Dumoulin C, Watkins R. Diffusion-weighted MRI after cryosurgery ofthe canine prostate. J Magn Reson Imaging 2003;17:131–135.

15. Jacobs MA, Herskovits EH, Kim HS. Uterine fibroids: diffusion-weighted MR imaging for monitoring therapy with focused ultrasoundsurgery—preliminary study. Radiology 2005;236:196–203.

16. Lang P, Wendland MF, Saeed M, Gindele A, Rosenau W, Mathur A,Gooding CA, Genant HK. Osteogenic sarcoma: noninvasive in vivoassessment of tumor necrosis with diffusion-weighted MR imaging.Radiology 1998;206:227–2335.

17. Geschwind JH, Artemov D, Abraham S, Omdal D, Huncharek MS,McGee C, Arepally A, Lambert D, Venbrux AC, Lund GB. Chemoem-bolization of liver tumor in a rabbit model: assessment of tumor celldeath with diffusion-weighted MR imaging and histologic analysis. JVasc Interv Radiol 2000;11:1245–1255.

18. Le Bihan D, Delannoy J, Levin RL. Temperature mapping with MRimaging of molecular diffusion: application to hyperthermia. Radiology1989;171:853–857.

19. MacFall J, Prescott DM, Fullar E, Samulski TV. Temperature depen-dence of canine brain tissue diffusion coefficient measured in vivo withmagnetic resonance echo-planar imaging. Int J Hyperthermia 1995;11:73–86.

20. Ross AB, Diederich CJ, Nau WH, Gill H, Bouley DM, Daniel B, Rieke V,Butts RK, Sommer G. Highly directional transurethral ultrasound ap-plicators with rotational control for MRI-guided prostatic thermal ther-apy. Phys Med Biol 2004;49:189–204.

21. Ross AB, Diederich CJ, Nau WH, Rieke V, Butts RK, Sommer G, Gill H,Bouley DM. Curvilinear transurethral ultrasound applicator for selec-tive prostate thermal therapy. Med Phys 2005;32:1555–1565.

22. Gudbjartsson H, Maier SE, Mulkern RV, Morocz IA, Patz S, Jolesz FA.Line scan diffusion imaging. Magn Reson Med 1996;36:509–519.

23. Gonzelez RC, Woods RE. Digital imaging processing, 2nd edition. Up-per Saddle River, NJ: Prentice Hall; 2001. p 595–608.

24. Rubinsky B. Cryosurgery. Annu Rev Biomed Eng 2000;2:157–187.25. Lyng H, Haraldseth O, Rofstad EK. Measurement of cell density and

necrotic fraction in human melanoma xenografts by diffusion weightedmagnetic resonance imaging. Magn Reson Med 2000;43:828–836.

26. Coad JE, Bischof JC. Histologic differences between cryothermic andhyperthermic therapies. Proc SPIE, 2003;4954:27–36.

27. Moseley ME, Cohen Y, Mintorovitch J, Chileuitt L, Shimizu H, Kucha-rczyk J, Wendland MF, Weinstein PR. Early detection of regional cere-bral ischemia in cats: comparison of diffusion- and T2-weighted MRIand spectroscopy. Magn Reson Med 1990;14:330–346.

28. MacFall JR, Maki JH, Johnson GA, Hedlund LW, Cofer GP. Pre- andpostmortem diffusion coefficients in rat neural and muscle tissues.Magn Reson Med 1991;20:89–99.

29. Wheatley DN, Redfern A, Johnson RP. Heat-induced disturbances ofintracellular movement and the consistency of the aqueous cytoplasmin HeLa S-3 cells: a laser-Doppler and proton NMR study. PhysiolChem Phys Med NMR 1991;23:199–216.

30. Marks MP, de Crespigny A, Lentz D, Enzmann DR, Albers GW, MoseleyME. Acute and chronic stroke: navigated spin-echo diffusion-weightedMR imaging. Radiology 1996;199:403–408.

31. Hazle JD, Diederich CJ, Kangasniemi M, Price RE, Olsson LE, StaffordRJ. MRI-guided thermal therapy of transplanted tumors in the canineprostate using a directional transurethral ultrasound applicator. J MagnReson Imaging 2002;15:409–417.

32. Liu C, Bammer R, Kim DH, Moseley ME. Self-navigated interleavedspiral (SNAILS): application to high-resolution diffusion tensor imag-ing. Magn Reson Med 2004;52:1388–1396.

33. Liu C, Moseley ME, Bammer R. Simultaneous phase correction andSENSE reconstruction for navigated multi-shot DWI with non-Carte-sian k-space sampling. Magn Reson Med 2005;54:1412–1422.

34. Butts K, Pauly JM, de Crespigny A, Moseley ME. Isotropic diffusion-weighted and spiral-navigated interleaved EPI for routine imaging ofacute stroke. Magn Reson Med 1997;38:741–749.

35. Bammer R, Keeling SL, Augustin M, Pruessmann KP, Wolf R, Stoll-berger R, Hartung HP, Fazekas F. Improved diffusion-weighted single-shot echo-planar imaging (EPI) in stroke using sensitivity encoding(SENSE). Magn Reson Med, 2001;46:548–554.

36. Pipe JG. Motion correction with PROPELLER MRI: application to headmotion and free-breathing cardiac imaging. Magn Reson Med 1999;42:963–969.

1372 Chen et al.